Nationwide Incidence and Clinical Outcomes of COVID-19 Vaccination-Related Myocarditis in Korea

Vaccine-related myocarditis (VRM) is a rare but concerning complication following COVID-19 vaccination. Previous studies, primarily cohort studies and epidemiological analyses, have linked VRM to mRNA vaccines, particularly in young males, often developing within a week of vaccination. Reported incidences vary widely (1.4–5.0 per 100,000 vaccinated persons) due to differences in study populations and methodologies. While generally mild, some cases have shown severe outcomes, including fulminant myocarditis and death, highlighting the need for comprehensive nationwide studies to accurately assess incidence and clinical course. The Korean Disease Control and Prevention Agency (KDCA) established a national reporting system for COVID-19 vaccination adverse events, providing a unique opportunity to analyze VRM in the entire vaccinated Korean population and minimize selection bias. This study aims to determine the nationwide incidence and clinical outcomes of COVID-19 VRM in Korea, utilizing the KDCA's comprehensive data.

Existing literature on COVID-19 vaccine-related myocarditis reveals a range of reported incidences, from 1.4 to 5.0 cases per 100,000 vaccinated individuals. These variations are attributed to differences in study populations, vaccine types, and the observation periods for myocarditis onset. While many studies suggest that VRM is predominantly associated with mRNA vaccines and young males, the clinical courses are generally described as mild with favorable short-term outcomes. However, cases of severe VRM, including fulminant myocarditis and death, have been reported, emphasizing the need for further large-scale investigations to clarify the incidence and severity of this complication.

This retrospective nationwide study utilized data from the KDCA's national reporting system on COVID-19 vaccination adverse events, encompassing the entire Korean vaccinated population (over 44 million individuals). The KDCA's Expert Adjudication Committee reviewed reported cases of suspected myocarditis/pericarditis, applying the Brighton Collaboration (BC) case definition with modifications to minimize misdiagnosis. Cases were excluded if they met only the less stringent BC level 3 criteria (without elevated cardiac troponin) or had a positive COVID-19 infection. The committee thoroughly investigated other potential causes of myocarditis, including viral antibody and autoimmune marker testing. The study analyzed demographic characteristics, vaccine type, time to symptom onset, clinical presentation, laboratory findings (cardiac troponin levels), ECG, echocardiography, and cardiac magnetic resonance (CMR) data. Severe VRM was defined as cases requiring ICU admission, fulminant myocarditis, ECMO, death, or heart transplantation. Statistical analyses included descriptive statistics, chi-square tests, Fisher's exact tests, Kaplan-Meier analysis, ROC curve analysis, and binary logistic regression to identify independent predictors of severe VRM. Autopsy reports were reviewed for sudden cardiac death (SCD) cases. The study received ethical approval from the KDCA's IRB.

Among 1533 reported cases of suspected acute myocarditis, the Expert Adjudication Committee confirmed 480 cases of COVID-19 VRM (1.08 per 100,000 vaccinated persons). VRM was significantly more common in males (62.3%), individuals under 40 years (67.9%), and after mRNA vaccination (96.3%). The most frequent symptom was chest pain or discomfort; the median time from vaccination to symptom onset was 3 days. The incidence was significantly higher in men (1.35 per 100,000) than women (0.82 per 100,000) and higher with mRNA vaccines (1.46 per 100,000) compared to other vaccines (0.14 per 100,000). The highest incidence was observed in males aged 12–17 years (5.29 per 100,000). Severe VRM occurred in 95 cases (19.8%), comprising 85 ICU admissions, 36 fulminant myocarditis cases, 21 ECMO therapies, 21 deaths, and 1 heart transplantation. Eight deaths were confirmed by autopsy as SCD attributable to VRM, all in individuals under 45 years who received mRNA vaccines. Cardiac troponin was elevated in 96.7% of VRM cases. ECG abnormalities were common, and LVEF <50% was found in 23.2% of echocardiography cases. CMR imaging confirmed acute myocarditis in 72.7% of cases. Low systolic blood pressure (<100 mmHg) and older age (>40 years) were independent predictors of severe VRM. The incidence of VRM after the third dose was significantly lower (0.24 per 100,000) than after the first or second dose.

This nationwide study provides valuable insights into COVID-19 VRM. The observed incidence of 1.08 cases per 100,000 vaccinated persons, while rare, is higher than some previous reports and highlights the importance of robust surveillance systems. The findings confirm the association of VRM with mRNA vaccines and young males, but also reveal unique characteristics in the Korean population, such as a less pronounced male predominance and higher incidence in older age groups (40-60 years). The significant proportion of severe VRM cases (19.8%) and the eight autopsy-confirmed SCDs emphasize the potential severity of this complication. The discrepancy in the proportion of severe VRM cases compared to other studies may be partly attributed to the comprehensive national reporting and causality assessment system in Korea, minimizing underreporting. The study also highlights the need for vigilant monitoring of SCD, particularly in younger individuals who received mRNA vaccines. These findings reinforce recommendations for careful post-vaccination monitoring, particularly in high-risk groups.

COVID-19 VRM remains a rare but potentially serious complication of COVID-19 vaccination, predominantly associated with mRNA vaccines and younger males. Although the overall incidence was low, a substantial proportion of cases developed severe complications, including sudden cardiac death. The findings emphasize the necessity of continued surveillance and careful monitoring of high-risk individuals to detect and manage this adverse event effectively. Future research could investigate potential mechanisms of severe VRM and explore targeted preventive strategies.

This study acknowledges several limitations. Despite efforts to minimize underreporting, the inherent limitations of a reporting system may lead to underestimation of VRM incidence. Furthermore, not all cases underwent thorough etiological investigation, potentially leading to misclassification. Data limitations regarding echocardiography and CMR availability may also influence the findings. Finally, the lack of data on unvaccinated individuals prevents the identification of independent predictors for VRM in the entire population. However, the study's strength lies in its large sample size and the comprehensive data provided by the KDCA's national reporting system.